Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice
Xiuwei Tang, … , David R. Bickers, Mohammad Athar
Xiuwei Tang, … , David R. Bickers, Mohammad Athar
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):867-875. https://doi.org/10.1172/JCI20732.
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Article Dermatology

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

Abstract

Solar ultraviolet B (UVB) radiation induces cutaneous ornithine decarboxylase (ODC), the first enzyme in the polyamine-biosynthesis pathway, which drives continued proliferation and clonal expansion of initiated (mutated) cells, leading to tumorigenesis. Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH). To assess this possibility, we first overexpressed ODC in the skin of Ptch1+/– mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle. UVB irradiation of these mice accelerated induction of BCCs as compared with their Ptch1+/– littermates. To further verify the role of ODC in BCC tumorigenesis, we used an antizyme (AZ) approach to inhibit ODC activity in the Ptch1+/– mice. Ptch1+/– mice with AZ overexpression driven by the K6 promoter were resistant to the induction of BCCs by UVB. Furthermore, oral administration of the suicidal ODC inhibitor α-difluoromethylornithine reduced UVB-induced BCCs in Ptch1+/– mice. These results demonstrate the crucial importance of ODC for the induction of BCCs and indicate that chemopreventive strategies directed at inhibiting this enzyme may be useful in reducing BCCs in human populations.

Authors

Xiuwei Tang, Arianna L. Kim, David J. Feith, Anthony E. Pegg, Justin Russo, Hong Zhang, Michelle Aszterbaum, Levy Kopelovich, Ervin H. Epstein Jr., David R. Bickers, Mohammad Athar

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Effect of DFMO on UVB-induced skin tumorigenesis in Ptch1+/– mice. (A) E...
Effect of DFMO on UVB-induced skin tumorigenesis in Ptch1+/– mice. (A) Effect of DFMO administration on the growth of UVB-induced skin tumors. The experiment was terminated at week 52. (B) Mice showing the effect of DFMO treatment on UVB-induced skin tumors. Left: UVB-treated control. Right: mouse treated with UVB plus DFMO, shown at week 52. (C) Effect of orally administered DFMO on the growth of UVB-induced BCCs, SCCs, and fibrosarcomas. *P < 0.025. **P < 0.05. (D) β-Gal (blue) and H&E (red) staining showing the effect of orally administered DFMO on UVB-induced microscopic BCC-like lesions in Ptch1+/– mice. Upper panel: skin section from UVB-irradiated Ptch1+/– mouse. Lower panel: skin section from UVB-irradiated DFMO-treated Ptch1+/– mouse. (E) Effect of orally administered DFMO on UVB-induced microscopic BCC-like lesions in Ptch1+/– mice. Samples of full-thickness dorsal skin were fixed in 10% buffered formalin and stained with H&E and β-gal, and microscopic BCC-like lesions were measured as total tumor area per square millimeter skin sample.